Physiological changes including menopause and ovariectomy induce irreversible changes in the cardiovascular system that frequently result in diminished endothelium-dependent regulation of vascular tone and can lead to hypertension. Ca2+ signaling in vascular endothelium is a key regulator for many of the endothelium-derived vasoactive factors, including endothelins, prostaglandins, nitric oxide, and endothelium- derived hyperpolarizing factor (EDHF). Several K+ channels are expressed in vascular endothelium that contribute differently to Ca2+ signaling due in large part to their characteristic biophysical properties and sub- cellular localizations. Recent work demonstrates that SK3 (small-conductance Ca2+-activated K+, subtype 3) channels play a crucial role in EDHF-mediated vasorelaxation, influencing vascular tone and blood pressure. The goal of this proposal is to determine the cellular and molecular mechanisms through which SK3 channels regulate vascular tone, and how estrogen modulates SK3 channel activity and EDHF-induced vasodilation. Dr. John Adelman is an internationally recognized scientist in SK channel research and will provide primary mentoring guidance that will be complemented by a team of co-mentors and consultants, reflecting the strengths of the OHSU community. Hypertension, the so-called "silent killer", is a profound and widespread health issue, and is a major risk factor that can further lead to cardiovascular morbidity and mortality, the number one cause of death in developed countries. Understanding endothelial SK3 channel function, expression, distribution, and regulation may reveal novel therapeutic strategies for the treatment against hypertension and its deleterious sequelae, improving the quality of life for a significant population. ) PUBLIC HEALTH RELEVANCE: Cardiovascular disease is the leading cause of death in the United States. Post-menopause, aging, and hypertension are all major risk factors of cardiovascular disease morbidity and mortality. Age-matched men are generally at greater risk than premenopausal women for cardiovascular disease;however, after menopause women lose their cardioprotection. This proposal is designed to test the hypothesis that estrogen regulates endothelial potassium channels to modulate vascular reactivity and blood pressure.)